Targeting apoptosis resistance in CRPC

Enzalutamide resistance is emerging as a clinically important obstacle to prostate cancer therapy. A new preclinical report identified BIRC6, a member of the inhibitor of apoptosis protein (IAP) family, as a possible target for the treatment of castration-resistant prostate cancer (CRPC) that is also resistant to enzalutamide.

The team from Vancouver, Canada, set out to investigate whether pathways other than those related to androgen receptor (AR) signalling were involved in conferring treatment resistance to AR-targeting drugs in CRPCs. For their studies, they developed an in vivo prostate cancer model of patient-derived xenografts (PDXs), consisting of the hormone-naive line LTL-313B and a castration-resistant and enzalutamide-resistant subline LTL-313BR. Evaluation of mRNA and protein levels of IAPs in mice with LTL-313BR PDXs showed increased expression of BIRC6. Treatment of these mice with an antisense oligonucleotide that targets BIRC6 resulted in inhibited tumour growth, reduced increases in PSA levels and elevated tumour apoptosis compared with controls, without considerable toxic effects.

Analysis of RNA levels in these PDXs showed that BIRC6-targeted antisense oligonucleotide treatment led to downregulation of gene expression of prosurvival pathway members such as IGFBP5 and BCL2 that were elevated in the enzalutamide-resistant PDX subline compared with the LTL-313B line. Furthermore, pathway enrichment analysis revealed generally reduced G-protein-coupled receptor activation and deregulation of matrisome pathways in the antisense-treated PDX model.

Taken together, these results indicate that AR-signalling-unrelated pathways support survival of enzalutamide-resistant CRPCs and that targeting of the IAP BIRC6 might be a possibility in the treatment of these tumours.